9-(n-substituted-omega-aminoalkyl)-pyrid [3, 4-b] indoles and intermediate



United States Patent 9-(N-SUBSTITUTED-w-AMINOALKYL)-PYRID [3,4-b1INDOLESAND INTERMEDIA'I'E Richard A. Robinson, Evanston, 111., assignor to G.D. Searle & Co., Chicago, 11]., a corporation of Delaware No Drawing.Filed Apr. 15, 1959, Ser. No. 806,446

10 Claims. (Cl. 260-496) This invention relates to novel heterocyclicnitrogen compounds and more particularly to 9-pyrid-[3,4-b]- indoleswhich contain an N-substituted-w-amino-alkyl substituent in the9-position and also to a novel intermediate in the preparation of same.Alternate names which can be used to indicate the parent ring structureof the present compounds are B-carboline and norharman. The compounds ofthe present invention can be represented by the structural formulawherein A is an alkylene radical containing fewer than carbon atoms, Alkis an alkylene radical containing fewer than 4 carbon atoms andoptionally substituted by an hydroxyl group, and R is selected from thegroup consisting of methoxyphenyl, dimethoxyphenyl, trimethoxy phenyl,phenyl, halophenyl, aminophenyl, dihydroxyphenyl, and dibenzyloxyphenylradicals.

The lower alkylene radicals which may be represented by A are, forexample:

-CH2 H-(L2-propylene) v -CH2OHzCHgCHz-(tetramethylene) The term Alk asdefined herein is exemplified by the following groups:

-CH -(methy1ene) CH2CHz-(ethylene) CHqCHzCHz-(trimethylene) C H;(1,2-propy1ene) -0 Hz J] H- I (hydroxyethylenQ-CHMH- CH3 ()H(1hydroxy-1,2-propyleue)-(EBB-OH- "ice Y The instant9-(N-substituted-w-aminoalkyl)-9pyrid[3,4-

b]indoles can be prepared by reacting the aforementioned(methoxybenzylamino)propyl]-9-pyrid[3,4-b]indole. Re

. action of an ether solution of this base with hydrogen chlorideaflords the corresponding dihydrochloride.

The preferred process for the preparation of the instant compoundsinwhich R is an aminophenyl moiety involves the use of a nitrophenylcarbonyl intermediate.

1 Thus, the nitro group is reduced during the reaction.

The compounds of this invention in which R is a dihydroxyphenyl groupare conveniently prepared by hydrogenolysis of the correspondingdibenzyloxyphenyl compounds. For example, 9 [33,4-dlbeI1ZY10XY-umethylphenethylamino)propyl]-9-pyrid[3,4 b]indole inmethanol is reacted with hydrogen at 1-3 atmospheres pressure in thepresence of a 10% palladium-on-carbon catalyst to afford9-[3-(3,4-dihydroxy-u-methylphenethylamino) propyl] -9-pyrid [3,4-b]indole.

The 9-(N-substitutedv-aminoalkyl) 9 pyrid[3,4-b]- indoles of thisinvention are useful as a result of their valuable pharmacologicalproperties. They have, for example, the ability to potentiate thesleep-producing activity of. barbiturate sedatives. They arealsoantiinflamrnatory agents, as evidenced by their ability to inhibit thelocal edema formation associated'with inflammatory states. In addition,they are hypotensive agents.

As is demonstrated supra, 9-(3-aminopropyl)-9-pyrid [3,4-b]indole isuseful as an intermediate in the manufacture of the97(N-substituted-3-aminopropyl)-9-pyrid- [3,4-b]indoles of thisinvention. This invention will appear more fully from the examples whichfollow. These examples are set forth by way of illustration only and itwill be understood that the invention is' not to be construed as limitedin spirit or in scope by the details contained therein as manymodifications in materials and methods will be apparent in thisdisclosure to those skilled in the art. In these examples, temperaturesare given in degrees centigrade C.). Pressures are designated as poundsper square Quantities of materials are expressed in inch (p.s.i.). partsby weight unless otherwise noted.

EXAMPLE 1 1 9-(3-amin0propyl)-9-pyria [3,4-b]indole A mixture of 5.5parts of 9-(2-cyanoethyl)-9-pyrid[3,

4-b]indo1e, 2 parts of anhydrous potassium carbonate, 5

fication of the filtrate with sodium hydroxide, extraction of theliberated base into ether, evaporation of the ether and finallydistillation at 180-190/0.01 mm. to afford 9-(3-aminopropyl)-9-pyrid[3,4-b] indole.

An isopropanol solution of 9-(3-aminopropyl)-9-pyrid- [BA-b]indole istreated with a solution of hydrogen chloride in isopropanol. Theresultant precipitate is recrystallized from methanol to yield9-'(3-aminopr opyl)-9-pyrid [BA-b]indole dihydrochloride, M.P. 325.

3 EXAMPLE 2 9- [3-(3-methoxybenzylamino)propyl] -9-pyrid- [3,4-b1ind0leA mixture of 11.2 parts of 9-(3-aminopropyl)-9 pyrid- [3,4-b1indole, 7parts of S-methoxybenzaldehyde, 0.3 part of platinum oxide, and 200parts of methanol is stirred under hydrogen at one atomsphere ofpressure until one molecular equivalent of hydrogen is absorbed. Thecatalyst is removed by filtration and the solvent distilled at reducedpressure to afford the oily free base, 9-[3-(3- methoxybenzylaminopropyl] -9-pyrid [3 ,4-b] indole.

An ether solution of the oily base is treated with an isopropanolsolution of hydrogen chloride resulting in the precipitation of thecrude dihydrochloride. Recrystallization from methanol affords9-[3-(3-methoxybenzylamino)propyl] 9 pyrid[3,4-b]indole dihydrochloride,M.P. 242.

EXAMPLE 3 9- [3-(3,4,5-trimethoxybenzylamino) propyl] 9-pyrid[3,4-b1indole By substituting a mixture of 22.1 parts of9-(3-aminopropyl)-9-pyrid[3,4-b]indole, 20 parts of3,4,5-trimethoxybenzaldehyde, 0.4 part of platinum oxide, and 200 partsof methanol in the process described in Example 2;9-[3-(3,4,5-trimethoxybenzylamino)propyl] 9 pyrid- [3,4-b]indole and itsdihydrochloride, M.P. 260, are obtained.

EXAMPLE 4 9- [3-(4-methoxybenzylamino) propyl] -9-pyricl- [3,4-b] indoleBy substituting 4-methoxybenzaldehyde for S-methoxybenzaldehyde-in theprocess in Example 2, 9 [3 (4- methoxybenzylamino)propyl] 9pyrid[3,4-b]indole and its dihydrochloride, M.P. 232, are obtained.

EXAMPLE 5 9- [3- (3 -chl0r0benzylamino) propyl -9pyrid- [3,4-b1ind0leSubstituting of 3-chlorobenzaldehyde for 3-methoxybenzaldehyde in theprocedure of Example 2 aflords 9- [3-(3-chlorobenzylamino)propyl] 9pyrid[3,4-b]indole and its dihydrochlo'ride, M.P. 100.

By substituting an equivalent quantity of 3-iodobenz aldehyde andotherwise proceeding according to the hereindescribed processes,9-[3-(3-iodobenzylamino)propyl]- 9-pyrid[3,4-b]indole is obtained. Itexhibits maxima in the ultraviolet at about 289 and about 304millimicrons.

EXAMPLE 6 9- [3-(4-amin0benzylamino)propyl] -9-pyrid- [3,4-b1ind0leEXAMPLE 7 9- [3-(fi-hydroxy-a-mezhylphenethylamino) propyl] 9-pyrid[3,4-b] indole To a mixture of 33 parts of 9-(3-aminopropyl) -9-pyrid-[3,4-b1indole, 30 parts of (l) l-hydroxy-l-phenylpropanone-Z and 200.parts of methanol is added 0.4 part masses 4: '7 of platinum oxide andthe resultant mixture is shaken under one atmosphere of hydrogenpressure until one molecular equivalent of hydrogen is absorbed. Thecatalyst is removed by filtration and the solvent by evaporation invacuo, resulting in an oily reside. The residue is dissolved in etherand the ether solution treated with solid carbon dioxide to precipitatethe carbonate of unreacted 9-(3-arninopropyl) 9 pyrid[3,4-b]indole. Re-

' moval of the precipitate by filtration and evaporation of the solventyields 9 [3(fi-hydroxy-oc-methylphenethylamino)prepyl]-9-pyrid-[3,4-b]indolerepresented by the structural formula:

Treatment of an ether solution of the latter base with propanolichydrogen chloride afiords the dihydrochloride, M.P. about 200.

EXAMPLE 8 9- [3-(3,4-dimethoxyz-methylphenethylamino)- propyl] -9-pyrid[3 ,4-b] indole \1TI/\/ H (3115 onionioniN-t z-omgooni OCH:

Its dihydrochloride, M.P. 256, is prepared in the usual manner.

EXAMPLE 9 9-[3-(3,4-dibenzyloxy-a-methylphenezhylamina)- propyl]-9-pyrid [3,4-b] indole A mixture of 35 parts of9-(3-aminopropyl)-9-pyrid- [3,4-b1ind'ole, 52 parts of3,4-dibenzyloxyphenylacetone, 0.5 part of platinum'oxide, and 250 partsof methanol is hydrogenated at 15-45 p.s.i. until one molecularequivalent of hydrogen is absorbed. Isolation of the product by theprocedure described in previous examples results in 9[3-(3,4-dibenzyloxy a-methylphenethylamino)propyl]-9-pyrid[3,4-b]indoleand its dihydrochloride, M.P. 203.

EXAMPLE l0 9- [3 -(3 ,4-dz'hydroxy-u-methylphenethylamino) propyl9-pyrid [3,4 b] indole dihydrochloride a-methylphenethylamino) propyl]-9-pyrid [3 ,4 -b] indole dihydrochloride, M.P.

EXAMPLE 11 9- [3- (3,4-dibenzylxy-fi-hydroxy-u-meihylphenethylaminopropyl] -9-pyrid [3,4-b] indole A mixture of 22 parts of9-(3-aminopropyl)-9-pyrid- [3,4-b]indole, 37 parts of(l)l-(3,4-dibenzyloxyphenyl)-1-hydroxypropanone-2, 0.5 part of platinumoxide, and 250 parts of methanol is shaken in a hydrogen atmosphere at15-45 p.s.i. pressure until one equivalent of hydrogen is absorbed.Treatment of the mixture in the usual manner affords9-[3-(3,4-dibenzyloxy-B-hydroxy-u-methylphenethylamino)propyl]-9-pyrid[3,4b]- indole. Its dihydrochloride has a M.P. of about 180.

EXAMPLE 12 9- [3-( 5,3,4-trihydroxy-ot-methylphenethylamino propyl-9-pyrid [3 ,4-b] indole dihydrochloride A mixture of 55 parts of9-[3-(3,4dibenzyloxy-ahydroxy-/3-methylphenethylamino)propyl]9-pyrid[3,4- bJindole dihydrochloride, 1 part of 10% palladium-on carboncatalyst, and 250 parts of methanol is hydrogenated at -45 p.s.i. in theusual manner. Isolation of the product by the procedure described inExample 10 yields 9 [345,3,4-trihydroxy-a-methylphenethylamino)-propyl]-9-pyrid[3,4-b]indole dihydrochloride. It exhibits maxima in theultraviolet at about 289 and about 304 millimicrons.

EXAMPLE 13 9-[3-(13,3,4-trihydroxylphenethylamina)propyl]-9- pyrid[3,4-b] indole dihydrochloride A mixture of 22 parts of9-(3-aminopropyl)-9-pyrid- [3,4-b1indole, 35 parts of3,4-dibenzyloxyphenylglyoxal, 0.5 part of platinum oxide, and 250 partsof methanol is shaken in a hydrogen atmosphere at 30-45 p.s.i. until.two molecular equivalents of hydroben are absorbed.

The catalyst is removed by filtration and the filtrate evaporated todryness in vacuo to afiord 9-[3-([3,3,4-trihydroxyphenethylamino)propyl]9 pyrid[3,4-b]indole. Dissolution of the latter in isopropanol followedby treatment with propanolic hydrogen chloride yields the correspondingdihydrochloride, M.P. about 162.

A mixture of 50 parts of 9-[3-(,8,3,4-trihydroxyphenethylamino) propyl]-9-pyrid[3,4 b] indole dihydrochloride, 1 part of 10%palladium-on-carbon catalyst, and 250 parts of methanol is shaken in ahydrogen atmosphere at 30-45 psi. until two molecular equivalents ofhydrogen are absorbed. The catalyst and solvent are removed in themanner specified above and the residue recrystallized from amethanol-isopropanol solution to yield9-[3-(ii-3,4-trihydroxyphenethylamino) propyl1- 9-pyrid[3,4-b]indoledihydrochloride, MP. about What is claimed is:

l. 9-[3 (3 methoxybenzylamino)propyl] 9 pyrid- [3,4-b1indole.

2. 9-[3 (3,4,5 trimethoxybenzylarnino)propyl] 9- pyrid[3,4-b]indole.

3. 9-[3 (3 chlorobenzylamino)propyl] 9 pyrid- [3,4-b1indole.

4. 9-[3 (4 aminobenzylamino)propyl] 9 pyrid- [3,4-b]indole.

5. 9-[3 (,3 hydroxy a methylphenethylamino)-propyl]-9-pyrid[3,4-b]indole.

6. 9-[3 (3,4 dimethoxy-a-methylphenethylamino)- propyl] -9-pyrid [3,4-b] indole.

7. 9-[3 (3,4 dibenzyloxy a methylphenethyl)- propyl]-9-pyrid[3,4-b]indole.

8. 9 [3 (3,4 dihydroxy-a-rnethylphenethylamino)-propyl]-9-pyrid[3,4-b]indole.

9. 9-[3 (5,3,4 trihydroxy a methylphenethylamino propyl] -9-pyrid 3,4-b] indole.

10. A compound of the formula wherein R is selected from the groupconsisting of hydrogen and methyl, X is a member of the class consistingof hydrogen and hydroxy groups, n is selected from. the group consistingof 0 and 1, and Z is selected from the group of radicals consisting ofmonomethoxyphenyl, dimethoxyphenyl, trimethoxyphenyl, monohalophenyl,monoarninophenyl, phenyl, dibenzyloxyphenyl, and dihydroxyphenyl.

References Cited in the file of this patent UNITED STATES PATENTS2,767,179 Cavallito et al. Oct. 16, 1956

10. A COMPOUND OF THE FORMULA